Introduction: It remains unclear why age increases risk of Alzheimer's disease and why some people experience age-related cognitive decline in the absence of dementia. Here we test the hypothesis that resilience to molecular changes in synapses contribute to healthy cognitive ageing.
Methods: We examined post-mortem brain tissue from people in mid-life (n = 15), healthy ageing with either maintained cognition (n = 9) or lifetime cognitive decline (n = 8), and Alzheimer's disease (n = 13). Synapses were examined with high resolution imaging, proteomics, and RNA sequencing. Stem cell-derived neurons were challenged with Alzheimer's brain homogenate.
Results: Synaptic pathology increased, and expression of genes involved in synaptic signaling decreased between mid-life, healthy ageing and Alzheimer's. In contrast, brain tissue and neurons from people with maintained cognition during ageing exhibited decreases in synaptic signaling genes compared to people with cognitive decline.
Discussion: Efficient synaptic networks without pathological protein accumulation may contribute to maintained cognition during ageing.
ASJC Scopus subject areas
- Health Policy
- Developmental Neuroscience
- Clinical Neurology
- Geriatrics and Gerontology
- Cellular and Molecular Neuroscience
- Psychiatry and Mental health